Abstract

Introduction

A younger age at menarche and an older age at menopause are well established risk
factors for breast cancer. Recent genome-wide association studies have identified
several novel genetic loci associated with these two traits. However, the association
between these loci and breast cancer risk is unknown.

Methods

In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms
(SNPs) from the ReproGen Consortium that have been associated with age at menarche
and age at natural menopause, respectively, and assessed their associations with breast
cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and
34,174 controls in white women of European ancestry. In addition, we used these SNPs
to calculate genetic risk scores (GRSs) based on their associations with each trait.

Results

After adjusting for age and potential population stratification, two age at menarche
associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated
SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and
0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele
were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01
to 1.20), respectively, and were in the direction predicted by their associations
with age at menarche or age at natural menopause. These associations did not appear
to be attenuated by further controlling for self-reported age at menarche, age at
natural menopause, or known breast cancer susceptibility loci. Although we did not
observe a statistically significant association between any GRS for reproductive aging
and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95%
CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest
quintile.

Conclusions

Our study suggests that three genetic variants, independent of their associations
with age at menarche or age at natural menopause, were associated with breast cancer
risk and may contribute modestly to breast cancer risk prediction; however, the combination
of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not
appear to be useful for identifying a high risk subgroup for breast cancer.